396 McGARRY & FOSTER tion. 2 Similar but exaggerated changes take place in uncontrolled diabetes. These remarkable adaptations appear to be orchestrated primarily through changes in the tissue concentration of a single compound, malonyl-coenн zyme A (malonyl-CoA). Auxiliary control is effected through fluctuations in levels of fatty acyl-CoA and camitine. Available evidence indicates that these biochemical changes are hormonally induced, with the islet cell horн mones, insulin and glucagon, playing dominant roles. Essential features of the control system, as currently understood, are as follows. In the carbohydrate fed state (low [glucagon]:[insulin)) the direcн tion of fatty acid metabolism in liver is primarily toward synthesis. Under these conditions fatty acid oxidation is shut down because of the high tissue level of malonyl-CoA which acts as a potent inhibitor of camitine acylн transferase I, the enzyme catalyzing the initial step in the oxidative seн quence. Conversely, elevation of the [glucagon]:[insulin] ratio, as occurs in ketotic states, suppresses the synthesis of malonyl-Co A and lipogenesis with concomitant activation of fatty acid oxidation and ketogenesis. Simultaн neously, an increase in hepatic carnitine (mechanism unknown) and fatty acyl-CoA content further enhance, a-oxidation and the production of acetoacetic and 3-hydroxybutyric acids. The experiments that culminated in the above formulation, the finer details of the model, and recent studies designed to test its validity are the major focus of this review.